Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
Obesity is a condition in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, exceeds healthy limits. It is commonly defined as a body mass index (weight divided by height squared) of 30 kg/m2 or higher.
Although obesity is an individual clinical condition, some authorities view it as a serious and growing public health problem, particularly since excessive body weight has been linked to the onset of diseases such as cardiovascular diseases, insulin resistance, dyslipidemia, hypertension, diabetes mellitus type 2 and sleep apnea.
The prevalence of adult obesity has increased approximately 75% in the last quarter century (Flegal, K M et. al., (1999-2000), Prevalence and trends in obesity among US adults, JAMA 288:1723-1727). The prevalence of overweight and obese children is also increasing in both developed and developing countries (Mascie-Taylor, C G, and Karim, E, (2003), The burden of chronic disease, Science 302:1921-1922). Current therapies to treat obesity centre on lifestyle modifications, but for those individuals who do not respond to such treatment, or cannot adhere to lifestyle intervention programs, bariatric surgery is often used. As this is neither a feasible nor a desirable treatment for a pandemic, drug therapy is a viable intervention for those in whom lifestyle modification has failed. Currently, there are three obesity drugs commonly prescribed. Xenical (orlistat) is a gastrointestinal lipase inhibitor, Sibutramine, a monoamine reuptake inhibitor, and Rimonabant, the first of the endocannabinoid receptor agonists. Disappointingly, none has resulted in consistent and effective weight loss, and to date, all anti-obesity drug trials have been limited by their high attrition rates and lack of long-term morbidity and mortality data (Padwal, R S, and Majumdar, S R (2007) Drug treatment for obesity: orlistat, sibutramine, and rimonbant, Lancet 369:71-77). Importantly, these drugs do not act by increasing energy metabolism and, currently, this is the focus of many pharmaceutical approaches.
The discovery of leptin (Zhang, Y et. al. (1994) Positional cloning of the mouse obese gene and its human homologue, Nature 372:425-432, Halaas, J L et. al. (1995) Weight-reducing effects of the plasma protein encoded by the obese gene, Science 269:543-546) and the leptin receptor (Tartaglia, L A et. al., (1995) Identification and expression cloning of a leptin receptor, OB-R, Cell 83:1263-1271), over a decade ago, led to the hope that researchers had at last identified a highly effective molecule and/or pathway that could be targeted in the treatment of obesity. However, it soon became apparent that obesity, in which high circulating concentrations of leptin develop, resulted in leptin resistance whereby endogenous leptin was no longer effective (Van Heek, M et. al. (1997) Diet-induced obese mice develop peripheral, but not central, resistance to leptin, J. Clin. Invest. 99:385-390).
Over the past decade a metabolic role for gp130 receptor cytokines has been elucidated. Often termed the “interleukin (IL)-6 family” of cytokines these include IL-6, leukemia inhibitory factor (LIF), IL-11, oncostatin-M, cardiotrophin-1 and ciliary neurotropic factor (CNTF). In particular, CNTF and IL-6 enhance fat oxidation in skeletal muscle and increase insulin sensitivity in vivo, principally via the activation of AMP activated protein kinase (AMPK) in both animals and humans. These results have generated a great deal of excitement as gp130 receptor ligands are now becoming recognised as a potential therapeutic target for obesity-induced insulin resistance. However, despite these major advanced in the understanding of the molecular processes as to how gp130 receptor ligands may enhance insulin sensitivity and act as “anti-obesogenic” agents, clinical trials have not been successful. This has been due principally to two major complications. The first is that IL-6 is pro-inflammatory and while it has positive effects on energy balance and insulin sensitivity when administered acutely, it has negative effects on the progression of many diseases. Secondly, CNTF failed in clinical trials because patients developed antibodies to Axokine®, the human recombinant variant of CNTF (Ettinger, M P, et. al. (2003) Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study, JAMA 289: 1826-1832). This was not entirely surprising since CNTF lacks a secretory signal sequence peptide and, therefore, does not circulate. Still further, due to the low level of CNTF receptors present in the periphery and the lower level of affinity of CNTF for the more light expressed IL-6 receptor, quite high concentration of CNTF were required to be used.
Accordingly, there exists an ongoing need to develop new methods for treating obesity. In work leading up to the present invention it has been determined that in terms of the functioning of IL-6 and CNTF, the unwanted side effects known to be associated with the administration of these molecules can be minimised by activating the IL-6 receptor and facilitating induction of the subsequent signalling via a gp130/LIF receptor heterodimer, rather than the gp130 homodimer which is used by IL-6. The findings of the present invention have now facilitated the development of methodology for increasing lipid oxidation in mammals without the concomittant problems of the induction of an inflammatory state, or the use of high concentrations of cytokine of the generation of autoantibodies. Accordingly, there is now provided a means for therapeutically or prophylactically treating conditions associated with unwanted lipid accumulation.